Despite the availability of effective antibiotics, bacterial meningitis is still a devastating disease that threatens the lives of children and young adults. The case fatality rate of bacterial meningitis is very high, approximately 20%, with rapid clinical progression upon following infection, and many patients who recover are left with neurological sequelae. Although there are racial and geographical differences, meningitis due to N. meningitidis remains a leading cause of bacterial meningitis in the world, which includes the United States and European countries (Rosenstein, N. E., et al., N Engl J Med 344, 1378-1388. (2001)).
The complete genomes of both N. meningitidis serogroup A and B has been sequenced respectively (Parkhill, J., et al., Nature 404, 502-506. (2000); and Tettelin H, S. N., et al., Science 287, 1809-1815 (2000)). N. meningitidis is one of the most common causes of bacterial meningitis and is divided into 13 serogroups based on chemically and immunologically distinct capsular PSs. Five serogroups, designated A, B, C, Y, and W-135, has been classified as pathogens in humans. However, meningococcal group B strain accounts for approximately 50% of bacterial meningitis (Ala'Aldeen , D. D. A., et al., Journal of Infection 33, 153-157 (1996); Riedo, F. X., et al., Pediatr Infect Dis J 14, 643-657 (1995); and Rosenstein, N. E., et al., N Engl J Med 344, 1378-1388 (2001)). In comparison to other serogroups, serogroup B meningoccal disease is more prevalent in North America and Europe, for unknown reasons. This creates a public health problem in the United States and Europe.
To date, PS-based conjugate vaccines have failed due to the poor immunogenicity of the capsular PS of NMGB. NMGB PS is a homolinear polymer of N-acetyl (2-8) neuraminic acid, and is structurally similar to polysialic acid of neural cell adhesion molecules expressed in human neuronal tissue (Finne, J., et al., Lancet 2, 355-357 (1983)). Thus, NMGB PS has the potential to induce autoantibodies and lead to autoimmune responses (Finne, J., et al., J Immunol 138, 4402-4407 (1987); and Nedelec, J., et al., J Neuroimmunol 29, 49-56 (1990)). Therefore, such problems make it difficult to develop a vaccine against NMGB.
In an attempt to circumvent this problem, Jennings reported an innovative strategy for overcoming the poor immunogenicity to NMGB PS and the cross-reactivity to NCAM, by substitution of N-propionyl for N-acetyl groups of NMGB PS (Jennings, H. J., et al., JEM 165, 1207-1211 (1987)). N-propionyl neuraminic acid polymer is reported to induce antibodies that cause bacteriolysis in vitro, but a subset of antibodies elicited by N-propionyl neuraminic acid have anti-host antibody activity (Granoff, D. M., et al., Journal of Immunology 160, 5028-5036 (1998); and Pon, R. A., et al., J Exp Med 185, 1929-1938 (1997)). This has made a problem in vaccine stability.
Studies using anti-idiotypic antibodies have focused mostly on increasing the immune response to tumor specific antigens, which do not elicit effective immune response due to their poor immunogenicity, and on the production of bacterial vaccine. For example, anti-idiotypic antibody to the capsular PS of N. meningitidis serogroup C was prepared and immunization of its anti-idiotypic peptide conjugated with carrier protein could elicit Ab to kill the bacteria (Westerink, M. A. J., et al., Proc Natl Acad Sci USA 92, 4021-4025 (1995)). A further example is that the immunization of mice with bacteriophages containing single chain variable fragment (scFv), which was obtained from anti-idiotypic antibody to Streptococcus pneumoniae, showed protective effect against bacterial infection (Magliani, W., et al., Nat Med 4, 705-709 (1998)).
Based on the above references, this inventor developed anti-idiotypic antibody using the properties of HmenB3 in order to provide a vaccine capable of protecting against and treating group B meningococcal disease (Shin, J. S., et al., Infect Immun 69, 3335-3342 (2001)). HmenB3 is a MAb against NMGB PS, which kills NMGB and has no cross-reactivity to NCAM (Shin, J. S., et al., Infect Immun 69, 3335-3342 (2001)).